PROJECT SUMMARY Major depressive disorder (MDD) is a major global health concern and is directly linked to the development of cardiovascular disease (CVD). Although a number of factors may contribute, accumulating evidence from humans and rodent models indicates that neurovascular dysfunction plays a pathogenic role in MDD-CVD comorbidity. Reduced nitric oxide (NO) bioavailability has emerged as a key mechanism in depression-induced neurovascular dysfunction; however, the molecular mediators are unclear. Compelling evidence in rodent models suggests depression-induced reductions in NO bioavailability, secondary to increases in oxidant stress, mediate peripheral vascular and central neural dysfunction. However, few studies have directly examined the mechanisms underlying NO-mediated neurovascular dysfunction in otherwise healthy adults with MDD. Interestingly, premenopausal women have lower CVD risk than men, yet are more than twice as likely to suffer from MDD. Although these data strongly suggest sex differences in the pathophysiology of MDD-CVD comorbidity, no investigations have examined potential sex differences in the mechanistic underpinnings of neurovascular dysregulation in MDD. Using an innovative translational human approach that combines molecular and biochemical techniques, a comprehensive assessment of endothelial function (micro- and macro-vascular reactivity) and direct recordings of sympathetic nervous system activity, the goal of the proposed studies is to rigorously examine the mechanism(s) underlying neurovascular dysfunction in otherwise healthy adults with MDD. Accordingly, our overall hypothesis is that oxidant stress?induced dysregulation of NO, both peripherally and centrally, underlies neurovascular dysfunction in MDD, representing a mechanistic link between depressive symptoms and CVD risk. In Specific Aim 1, we will examine the mechanistic role of peripheral NO in mediating vascular dysfunction in men and women with MDD, with emphasis on the role of oxidant stress. In Specific Aim 2, we will examine the sympathoinhibitory role of central NO in adults with MDD, also with specific focus on the role of oxidant stress in contributing to aberrant sympathetic function. Finally, in Specific Aim 3, we will investigate the influence of chronic selective serotonin reuptake inhibitors for the treatment of MDD on peripheral and central NO function. In each aim, we will investigate sex differences in MDD-induced neurovascular dysfunction. The findings have the potential to significantly advance our understanding of the mechanisms of neurovascular dysfunction in MDD and may provide novel therapeutic targets to alleviate CVD risk in depressed adults. These projects will extend the applicant's training in integrative neuro-cardiovascular physiology by allowing her to learn additional techniques, including in vitro biochemical analyses of human vascular tissue and the assessment and evaluation of MDD via diagnostic psychiatric interviews. In summary, these studies have the potential to establish and advance a novel area of clinically relevant research, while simultaneously providing strong mentored training and guided professional development, tailored to transition the PI to independence. In addition, potential follow-up studies have been identified that will be critical elements in the applicant's career progression and will foster her long-term career goal of becoming an independent investigator.